The present invention relates to a method for screening for risk of Alzheimer's disease in a patient, and to a transgenic mammal carrying a mutated human gene associated with the development of Alzheimer's disease.
Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis.
Hereditary or familial Alzheimer's disease is an autosomal dominant form of localized amyloidosis. Patients with hereditary Alzheimer's disease typically develop three pathologic lesions: (i) senile plaques in the cerebral cortex characterized by a central amyloid core surrounded by dystrophic neurites; (ii) neurofibrillary tangles; and (iii) congophilic angiopathy of the leptomeningeal vessels. The amyloid deposits in the senile plaques and in the blood vessel walls contain a fibril subunit protein of 39 to 43 amino acid residues [See, G. G. Glenner and C. W. Wong, Biochem. Biophys., Res. Commun., 120, p. 885 (1984)], which is a portion of the carboxyl terminus of the amyloid precursor protein (APP). Sequence analysis of cDNA clones of APP has shown that there are multiple forms of mRNA which are the result of alternate splicing of a transcript from a single gene. See, J. Kang et al., Nature, 325, p. 733 (1987); P. Ponte et al., Ibid, 331, p. 525 (1988); R. E. Tanzi et al., Ibid, p. 528; N. Kitaguchi, Y. Takahashi, Y. Tokushima, S. Shiojiri, H. Ito, Ibid, p. 530; N. Kitaguchi et al., Biochim. Biophys. Acta, 1039, p. 105 (1990); and S. Yoshikai, H. Sasaki, K. Doh-ura, H. Furuya, Y. Sasaki, Gene 87, p. 257 (1990). Although the sequence of the APP gene from some patients with either sporadic or familial Alzheimer's disease is normal [See, D. Goldgaber, M. I. Lerman, O. W. McBridde, U. Saffotti, D. C. Gajdusek, Science 235, p. 887 (1987); R. E. Tanzi et al., ibid, p. 880; N. K. Robakis, N. Ramakrishna, G. Wolfe, H. M. Wisniewski, Proc. Natl. Acad. Sci. U.S.A., 84, p. 4190 (1987); H. G. Lemaire et al., Nucleic Acids. Res. 17, p. 51 (1989); and M. P. Vitek et al., Mol. Brain Res. 4, p. 121 (1988)], a cytosine to thymine missense mutation in the membrane-spanning domain of the APP gene (causing a valine to isoleucine change in the corresponding amino acid sequence of the encoded APP) has been identified in patients from several families with familial Alzheimer's disease. See, A. Goate et al., Nature 349, p. 704 (1991).